Debra Kristensen

Intradermal delivery of vaccines: potential benefits and current challenges

Delivery of vaccine antigens to the dermis and/or epidermis of human skin (i.e. intradermal delivery) might be more efficient than injection into the muscle or subcutaneous tissue, thereby reducing the volumes of antigen. This is known as dose-sparing and has been demonstrated in clinical trials with some, but not all, vaccines. Dose-sparing could be beneficial to immunization programmes by potentially reducing the costs of purchase, distribution and storage of vaccines; increasing vaccine availability and effectiveness. The data obtained with intradermal delivery of some vaccines are encouraging and warrant further study and development; however significant gaps in knowledge and operational challenges such as reformulation, optimizing vaccine presentation and development of novel devices to aid intradermal vaccine delivery need to be addressed. Modelling of the costs and potential savings resulting from intradermal delivery should be done to provide realistic expectations of the potential benefits and to support cases for investment. Implementation and uptake of intradermal vaccine delivery requires further research and development, which depends upon collaboration between multiple stakeholders in the field of vaccination.

Heat-stable measles vaccine produced by spray drying

A combination of unique stabilizers and mild spray drying process conditions was employed to produce heat-stable measles vaccine powder. Live attenuated measles vaccine from Serum Institute of India was formulated with pharmaceutically approved stabilizers, including sugars, proteins, amino acids, polymers, surfactants, and plasticizers, as well as charged ions. In addition, the effects of buffer salt and pH on the storage stability of measles virus were examined. The potency of the dried vaccine stored at several temperatures was quantified by TCID(50) assay on Vero cells. As a comparison to other process methods, lead formulations were also subjected to freeze drying and foam drying. The optimized measles vaccine formulation tested at 37 degrees C was stable for approximately 8 weeks (i.e. time for 1 log TCID(50) loss). The measles titer decreased in a bi-phasic manner, with initial rapid loss within the first week but relative stability thereafter. Key stabilizers identified during the formulation screening processes were L-arginine, human serum albumin, and a combination of divalent cations. Spray drying was identified as the optimal processing method for the preparation of dried vaccine, as it generally resulted in negligible process loss and comparable, if not better storage stability, with respect to the other processes. Processing methods and formulation components were developed that produced a measles vaccine stable for up to 8 weeks at 37 degrees C, which surpassed the WHO requirement for heat stability of 1 week at that temperature.

The imperative for stronger vaccine supply and logistics systems

With the introduction of new vaccines, developing countries are facing serious challenges in their vaccine supply and logistics systems. Storage capacity bottlenecks occur at national, regional, and district levels and system inefficiencies threaten vaccine access, availability, and quality. As countries adopt newer and more expensive vaccines and attempt to reach people at different ages and in new settings, their logistics systems must be strengthened and optimized. As a first step, national governments, donors, and international agencies have crafted a global vision for 2020 vaccine supply and logistics systems with detailed plans of action to achieve five priority objectives. Vaccine products and packaging are designed to meet the needs of developing countries. Immunization supply systems support efficient and effective vaccine delivery. The environmental impact of energy, materials, and processes used in immunization systems is minimized. Immunization information systems enable better and more timely decision-making. Competent and motivated personnel are empowered to handle immunization supply chain issues. Over the next decade, vaccine supply and logistics systems in nearly all developing countries will require significant investments of time and resources from global and national partners, donors, and governments. These investments are critical if we are to reach more people with current and newer vaccines.

Development of a freeze-stable formulation for vaccines containing aluminum salt adjuvants.

Vaccines containing aluminum salt adjuvants are prone to inactivation following exposure to freeze-thaw stress. Many are also prone to inactivation by heat. Thus, for maximum potency, these vaccines must be maintained at temperatures between 2 degrees C and 8 degrees C which requires the use of the cold chain. Nevertheless, the cold chain is not infallible. Vaccines are subject to freezing during both transport and storage, and frozen vaccines are discarded (under the best circumstances) or inadvertently administered despite potentially reduced potency. Here we describe an approach to minimize our reliance on the proper implementation of the cold chain to protect vaccines from freeze-thaw inactivation. By including PEG 300, propylene glycol, or glycerol in a hepatitis B vaccine, particle agglomeration, changes in the fluorescence emission spectrum--indicative of antigen tertiary structural changes--and losses of in vitro and in vivo indicators of potency were prevented following multiple exposures to -20 degrees C. The effect of propylene glycol was examined in more detail and revealed that even at concentrations too low to prevent freezing at -10 degrees C, -20 degrees C, and -80 degrees C, damage to the vaccine could be prevented. A pilot study using two commercially available diphtheria, tetanus toxoid, and acellular pertussis (DTaP) vaccines suggested that the same stabilizers might protect these vaccines from freeze-thaw agglomeration as well. It remains to be determined if preventing agglomeration of DTaP vaccines preserves their antigenic activity following freeze-thaw events.

Vaccine stabilization: Research, commercialization, and potential impact

All vaccines are susceptible to damage by elevated temperatures and many are also damaged by freezing. The distribution, storage, and use of vaccines therefore present challenges that could be reduced by enhanced thermostability, with resulting improvements in vaccine effectiveness. Formulation and processing technologies exist that can improve the stability of vaccines at temperature extremes, however, customization is required for individual vaccines and results are variable. Considerations affecting decisions about stabilization approaches include development cost, manufacturing cost, and the ease of use of the final product. Public sector agencies can incentivize vaccine developers to prioritize stabilization efforts through advocacy and by implementing policies that increase demand for thermostable vaccines.

A prefilled injection device for outreach tetanus immunization by Bolivian traditional birth attendants

This study evaluated the performance, acceptability, and appropriateness of a new, single-use, prefilled injection device called UniJect for an outreach immunization application. Between April and June 1995, UniJect devices were used by 36 traditional birth attendants to administer tetanus toxoid injections to 2,240 pregnant women during routine, antenatal home visits in the Northern, Ichilos, and Warnes Districts of Santa Cruz, Bolivia. Because tetanus toxoid is relatively heat stable, the traditional birth attendants were able to keep the tetanus toxoid-filled UniJect devices in their homes for up to one month without refrigeration. The devices were stored, transported, and disposed of in an outreach carrier designed to reduce the risks of improper handling and disposal. Data were collected from injection recipients, traditional birth attendants, and supervisors via observation, questionnaires, and post-study interviews. The performance of the UniJect device and its acceptability among all groups was very high. The traditional birth attendants used UniJect properly and safely; there were no reports or observations of device misuse, reuse, or needle-stick. Advantages cited included the fact that the device required no assembly, offered assured sterility, and reduced vaccine wastage sometimes associated with multi-dose vials. The ability to store and transport the vaccine-filled devices without ice also greatly simplified logistics.

Characterization of the freeze sensitivity of a hepatitis B vaccine

Recent studies have revealed that vaccines containing aluminum adjuvant are exposed to sub-zero temperatures while in the cold chain more frequently than was previously believed. This raises concerns that these freeze-sensitive vaccines may be damaged and offer inadequate protection. This study was undertaken to characterize the immediate qualitative changes of one such vaccine, hepatitis B, caused by freeze exposure. Hepatitis B vaccine was subjected to freezing temperatures ranging from 0°C to -20°C for up to three episodes with durations ranging from 1 hour to 7 days. The vaccine was analyzed for freezing point, particle size distribution, tertiary structure, and in vitro and in vivo potency. Whether or not hepatitis B vaccine freezes was shown to be dependent on an array of factors including temperature, rate of temperature change, duration of exposure, supercooling effects, and vibration. Vaccine exposed to “mild” freezing (-4°C or warmer) temperatures did not freeze and remained qualitatively unaltered. Single or repeated freezing events at temperatures of -10°C or lower were associated with aggregation of the adjuvant-antigen particles, structural damage of the antigen, and reduction of immunogenicity in mice. Damage to the vaccine increased with duration of freezing, lower temperature, and the number of freezing episodes. With vibration, vaccine froze at -6°C after 1 hour and damage occurred. Freezing and freeze damage to vaccines containing aluminum adjuvant represents a real risk to effectiveness of immunizations and should be prevented by strengthening the cold chain system or, alternatively, development of freeze-stable vaccine formulations.

Characterization of a thermostable hepatitis B vaccine formulation.

Cold chain requirements for vaccine storage and distribution are both economic and logistical burdens for immunization programs, especially those in lower-resource settings. Inadvertent exposure of vaccines to both heat and freezing temperatures within such cold chains are frequently occurring problems in both developing and industrialized countries. Here we report on a new hepatitis B vaccine formulation that is stable against repeated freezing at -20 degrees C and is also stable for 12 months at 37 degrees C. The thermostable vaccine contains all the components of the original vaccine plus 7.5% (v/v) propylene glycol, 40mM phosphate, and 40mM histidine with a final pH of 5.2. The propylene glycol is responsible for the freeze stability while the other components are essential for the heat stability. This formulation was found to be well tolerated in rabbits without any significant local or systemic side effects. The improved stability of this hepatitis B vaccine could be a key factor in ensuring vaccine effectiveness, extending immunization coverage, simplifying immunization logistics, and reducing the costs associated with the cold chain.

Thermostable formulations of a hepatitis B vaccine and a meningitis A polysaccharide conjugate vaccine produced by a spray drying method.

Thermostable vaccines promise to simplify the logistics of vaccine distribution and expand the immunization coverage. In this study, a pilot-scale spray drying process was developed and used to produce glassy state formulations of a recombinant hepatitis B (HepB) vaccine containing aluminum adjuvant and Neisseria meningitidis A (MenA) protein-polysaccharide conjugate vaccine, representing two common types of subunit vaccines in use today: the spray-dried HepB vaccine formulations were stable for at least 24 months at 37 degrees C while several MenA vaccine formulations exhibited complete stability at temperatures up to 60 degrees C. This study demonstrates the feasibility of producing thermostable vaccines with advanced processing and formulation technologies.

Estimating the costs of the vaccine supply chain and service delivery for selected districts in Kenya and Tanzania

Having data on the costs of the immunization system can provide decision-makers with information to benchmark the costs when evaluating the impact of new technologies or programmatic innovations. This paper estimated the supply chain and immunization service delivery costs and cost per dose in selected districts in Kenya and Tanzania. We also present operational data describing the supply chain and service delivery points (SDPs). To estimate the supply chain costs, we collected resource-use data for the cold chain, distribution system, and health worker time and per diems paid. We also estimated the service delivery costs, which included the time cost of health workers to provide immunization services, and per diems and transport costs for outreach sessions. Data on the annual quantities of vaccines distributed to each facility, and the occurrence and duration of stockouts were collected from stock registers. These data were collected from the national store, 2 regional and 4 district stores, and 12 SDPs in each country for 2012. Cost per dose for the supply chain and immunization service delivery were estimated. The average annual costs per dose at the SDPs were